Identifying Opportunities to Deliver High-Quality Cancer Care Across a Health System: A Clinical Responsibility.

OBJECTIVE: We examined process-related quality metrics for oral squamous cell carcinoma (OSCC) depending on treating facility type across a health system and region. STUDY DESIGN: Retrospective in accordance with Strengthening the Reporting of Observational Studies in Epidemiology guidelines. SETTING: Single health system and region. METHODS: Patients with OSCC diagnosed between 2012 and 2018 were identified from tumor registries of 6 hospitals (1 academic and 5 community) within a single health system. Patients were categorized into 3 care groups: (1) solely at the academic center, (2) solely at community facilities, and (3) combined care at academic and community facilities. Primary outcome measures were process-related quality metrics: positive surgical margin rate, lymph node yield (LNY), adjuvant treatment initiation ≤6 weeks, National Comprehensive Cancer Network (NCCN)-guideline adherence. RESULTS: A total of 499 patients were included: 307 (61.5%) patients in the academic-only group, 101 (20.2%) in the community-only group, and 91 (18.2%) in the combined group. Surgery at community hospitals was associated with increased odds of positive surgical margins (11.9% vs 2.5%, odds ratio [OR]: 47.73, 95% confidence interval [CI]: 11.2-275.86, P < .001) and lower odds of LNY ≥ 18 (52.8% vs 85.9%, OR: 0.15, 95% CI: 0.07-0.33, P < .001) relative to the academic center. Compared with the academic-only group, odds of adjuvant treatment initiation ≤6 weeks were lower for the combined group (OR: 0.30, 95% CI: 0.13-0.64, P = .002) and odds of NCCN guideline-adherent treatment were lower in the community only group (OR: 0.35, 95% CI: 0.18-0.70, P = .003). CONCLUSION: Quality of oral cancer care across the health system and region is comparable to or better-than national standards, indicating good baseline quality of care. Differences by facility type and fragmentation of care present an opportunity for bringing best in-class cancer care across an entire region.

De-Escalated Therapy and Early Treatment of Recurrences in HPV-Associated Head and Neck Cancer: The Potential for Biomarkers to Revolutionize Personalized Therapy.

Human papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) is the most common HPV-associated cancer in the United States, with a rapid increase in incidence over the last two decades. The burden of HPV+ HNSCC is likely to continue to rise, and given the long latency between infection and the development of HPV+ HNSCC, it is estimated that the effect of the HPV vaccine will not be reflected in HNSCC prevalence until 2060. Efforts have begun to decrease morbidity of standard therapies for this disease, and its improved characterization is being leveraged to identify and target molecular vulnerabilities. Companion biomarkers for new therapies will identify responsive tumors. A more basic understanding of two mechanisms of HPV carcinogenesis in the head and neck has identified subtypes of HPV+ HNSCC that correlate with different carcinogenic programs and that identify tumors with good or poor prognosis. Current development of biomarkers that reliably identify these two subtypes, as well as biomarkers that can detect recurrent disease at an earlier time, will have immediate clinical application.

Paclitaxel With or Without Cixutumumab as Second-Line Treatment of Metastatic Esophageal or Gastroesophageal Junction Cancer: A Randomized Phase II ECOG-ACRIN Trial.

BACKGROUND: Patients with advanced esophageal cancer carry poor prognoses; limited data exist to guide second-line therapy in the metastatic setting. Paclitaxel has been used yet is associated with limited efficacy. There is preclinical evidence of synergy between paclitaxel and cixutumumab, a monoclonal antibody targeting insulin-like growth factor-1 receptor. We conducted a randomized phase II trial of paclitaxel (arm A) versus paclitaxel plus cixutumumab (arm B) in the second-line for patients with metastatic esophageal or gastroesophageal junction (GEJ) cancers. METHODS: The primary endpoint was progression-free survival (PFS); 87 patients (43 in arm A, 44 in arm B) were treated. RESULTS: Median PFS was 2.6 months in arm A [90% CL 1.8-3.5] and 2.3 months in arm B [90% 2.0-3.5], P = .86. Stable disease was observed in 29 (33%) patients. Objective response rates for Arms A and B were 12% [90% CI, 5-23%] and 14% [90% CI, 6-25%]. Median overall survival was 6.7 months [90% CL 4.9-9.5] in arm A and 7.2 months [90% CL 4.9-8.1] in arm B, P = 56. CONCLUSION: The addition of cixutumumab to paclitaxel in second-line therapy of metastatic esophageal/GEJ cancer was well tolerated but did not improve clinical outcomes relative to standard of care (ClinicalTrials.gov Identifier: NCT01142388).

Screening for extranodal extension in HPV-associated oropharyngeal carcinoma: evaluation of a CT-based deep learning algorithm in patient data from a multicentre, randomised de-escalation trial.

BACKGROUND: Pretreatment identification of pathological extranodal extension (ENE) would guide therapy de-escalation strategies for in human papillomavirus (HPV)-associated oropharyngeal carcinoma but is diagnostically challenging. ECOG-ACRIN Cancer Research Group E3311 was a multicentre trial wherein patients with HPV-associated oropharyngeal carcinoma were treated surgically and assigned to a pathological risk-based adjuvant strategy of observation, radiation, or concurrent chemoradiation. Despite protocol exclusion of patients with overt radiographic ENE, more than 30% had pathological ENE and required postoperative chemoradiation. We aimed to evaluate a CT-based deep learning algorithm for prediction of ENE in E3311, a diagnostically challenging cohort wherein algorithm use would be impactful in guiding decision-making. METHODS: For this retrospective evaluation of deep learning algorithm performance, we obtained pretreatment CTs and corresponding surgical pathology reports from the multicentre, randomised de-escalation trial E3311. All enrolled patients on E3311 required pretreatment and diagnostic head and neck imaging; patients with radiographically overt ENE were excluded per study protocol. The lymph node with largest short-axis diameter and up to two additional nodes were segmented on each scan and annotated for ENE per pathology reports. Deep learning algorithm performance for ENE prediction was compared with four board-certified head and neck radiologists. The primary endpoint was the area under the curve (AUC) of the receiver operating characteristic. FINDINGS: From 178 collected scans, 313 nodes were annotated: 71 (23%) with ENE in general, 39 (13%) with ENE larger than 1 mm ENE. The deep learning algorithm AUC for ENE classification was 0·86 (95% CI 0·82-0·90), outperforming all readers (p<0·0001 for each). Among radiologists, there was high variability in specificity (43-86%) and sensitivity (45-96%) with poor inter-reader agreement (κ 0·32). Matching the algorithm specificity to that of the reader with highest AUC (R2, false positive rate 22%) yielded improved sensitivity to 75% (+ 13%). Setting the algorithm false positive rate to 30% yielded 90% sensitivity. The algorithm showed improved performance compared with radiologists for ENE larger than 1 mm (p<0·0001) and in nodes with short-axis diameter 1 cm or larger. INTERPRETATION: The deep learning algorithm outperformed experts in predicting pathological ENE on a challenging cohort of patients with HPV-associated oropharyngeal carcinoma from a randomised clinical trial. Deep learning algorithms should be evaluated prospectively as a treatment selection tool. FUNDING: ECOG-ACRIN Cancer Research Group and the National Cancer Institute of the US National Institutes of Health.

The Quest to Eradicate HPV-Related Oropharyngeal Carcinoma: An Opportunity Not to Miss.

Oropharyngeal squamous cell carcinoma (OPSCC) accounts for more than half of all head and neck cancers. Since the 1970s, OPSCC has shifted from an environmentally triggered to virally mediated disease due to a sharp rise in human papillomavirus (HPV)-related squamous cell carcinoma. Although a highly effective prophylactic vaccine is available, its current implementation is far below national targets, and OPSCC incidence is predicted to further increase by 2045. However, we believe that with prompt action now, we can not only defy these predictions but also effectively eradicate HPV-related OPSCC in these next 20 years. We herein provide an overview of the necessary elements to eliminate this disease: improved primary vaccine uptake, a 1-time universal vaccination effort, and implementation of novel therapeutics that have potential to cure existing disease.

Guideline - Adherence in advanced stage head and neck cancer is associated with improved survival - A National study.

OBJECTIVES: Understanding the prevalence of guideline non-adherence among patients with advanced head and neck cancer (HNC) and its impact on survival may facilitate increased adherence. Our objective was to perform a detailed analysis of overall National Comprehensive Care Network (NCCN) guideline adherence in a national cohort. METHODS: Using the National Cancer Database, we analyzed site-specific NCCN guideline adherence for treatment of 100,074 overall stage III and IVA HNC patients from 2004 to 2013. Main outcomes were guideline adherence rates and overall survival (OS). Adherence was categorized by treatment: surgery/ radiation. Reasons were categorized as: (1) high risk; (2) refusal; (3) not planned. RESULTS: After exclusion, the care of 25,620 patients was defined as non-adherent (25.6%), yet adherence rates significantly improved across the study's years. After multivariate analysis, non-adherence was associated with age ≥ 65, female gender, black race, comorbidity score ≥ 1, insurance status, clinical staging, primary site, and facility type. Patients not managed according to NCCN guidelines had a significantly reduced OS compared with patients treated on-guideline (hazard ratio (HR) = 1.51 (95 %CI 1.48-1.54), p < 0.001). 'Not planned' patients had reduced OS when compared to adherent patients (HR = 1.27 (95 %CI 1.23-1.30), p < 0.001). Off-guideline treated patients due to 'risk factors' had a decrease in overall survival (OS) compared with other reasons (p < 0.001 for all). CONCLUSIONS: Despite improvement over time, non-adherence to NCCN guidelines for advanced stage HNC remains high. Non-adherence is associated with decreased OS, regardless of the reason. Despite concerns from both patient and physician, efforts should be made to increase guideline awareness and adherence.

Epigenetic age acceleration, fatigue, and inflammation in patients undergoing radiation therapy for head and neck cancer: A longitudinal study.

BACKGROUND: The authors measured epigenetic age acceleration (EAA) during and after cancer treatment and its association with inflammation and fatigue, which is a debilitating symptom in patients with cancer. METHODS: Patients who had head and neck cancer without distant metastases were assessed before, immediately after, and at 6 months and 12 months postradiotherapy. Blood DNA methylation was assessed using a proprietary bead chip (the Illumina MethylationEPIC BeadChip). EAA was calculated using the Levine epigenetic clock (DNAmPhenoAge), adjusted for chronological age. Fatigue was assessed using the Multidimensional Fatigue Inventory-20. Inflammatory markers were measured using standard techniques. RESULTS: Most patients (N = 133) were men, White, had advanced disease, and received concurrent chemoradiation. EAA changes over time were significant, with the largest increase (4.9 years) observed immediately after radiotherapy (P < .001). Increased EAA was associated with elevated fatigue (P = .003) over time, and patients who had severe fatigue experienced 3.1 years higher EAA than those who had low fatigue (P < .001), which was more prominent (5.6 years; P = .018) for patients who had human papillomavirus-unrelated disease at 12 months posttreatment. EAA was also positively associated with inflammatory markers, including C-reactive protein (CRP) and interleukin-6 (IL-6), over time (P < .001), and patients who had high CRP and IL-6 levels exhibited increases of 4.6 and 5.9 years, respectively, in EAA compared with those who had low CRP and IL-6 levels (P < .001). CRP and IL-6 mediated the association between EAA and fatigue (CRP: 95% CI, 0.060-0.279; IL-6: 95% CI, 0.024-0.220). CONCLUSIONS: Patients with head and neck cancer experienced increased EAA, especially immediately after treatment completion. EAA was associated with greater fatigue and inflammation, including 1 year after treatment. Inflammation may be a target to reduce the impact of age acceleration on poor functional outcomes.

STING enhances cell death through regulation of reactive oxygen species and DNA damage.

Resistance to DNA-damaging agents is a significant cause of treatment failure and poor outcomes in oncology. To identify unrecognized regulators of cell survival we performed a whole-genome CRISPR-Cas9 screen using treatment with ionizing radiation as a selective pressure, and identified STING (stimulator of interferon genes) as an intrinsic regulator of tumor cell survival. We show that STING regulates a transcriptional program that controls the generation of reactive oxygen species (ROS), and that STING loss alters ROS homeostasis to reduce DNA damage and to cause therapeutic resistance. In agreement with these data, analysis of tumors from head and neck squamous cell carcinoma patient specimens show that low STING expression is associated with worse outcomes. We also demonstrate that pharmacologic activation of STING enhances the effects of ionizing radiation in vivo, providing a rationale for therapeutic combinations of STING agonists and DNA-damaging agents. These results highlight a role for STING that is beyond its canonical function in cyclic dinucleotide and DNA damage sensing, and identify STING as a regulator of cellular ROS homeostasis and tumor cell susceptibility to reactive oxygen dependent, DNA damaging agents.

ECOG-ACRIN 2399: analysis of patient related outcomes after Chemoradiation for locally advanced head and neck Cancer.

BACKGROUND: We conducted a correlative study for E2399, a function preservation trial for resectable locally advanced oropharynx and larynx cancer, to prospectively assess effects of chemoradiation (CCR) on quality of life (QOL), swallowing and voice. We correlated the results of swallow assessments done via questionnaires and objective assessments by modified barium swallow (MBS). METHODS: The Functional Assessment of Cancer-HN (FACT-HN), the Performance Status Scale - Head and Neck (PSS-HN), swallow assessments (including modified barium swallow studies), and voice assessments: Voice Handicap Index (VHI), the Voice Disability Assessment (VDA), and American Speech-Language Hearing Association's Functional Communication Measure (FCM) were conducted at baseline and periodically post-treatment for 2 years. RESULTS: Baseline QOL and swallowing function predicted overall survival. Patients experienced a marked decrease in QOL, swallowing, and speech post CCR although the decrease in vocal function was modest. Function and QOL returned towards baseline in the majority of patients by 12 months post treatment. Less than 10% of patients had severe dysphagia and were PEG dependent at 12 months post treatment. There was a high degree of correlation between the FACT-HN and PSS-HN swallow items. Statistically significant correlations were found between subjective and objective measures of swallow function. CONCLUSIONS: Patients experience marked loss in swallowing function post CCR which returned to baseline in the majority of patients. The correlations between the FCM and self-report swallow items on the PSS and FACT-HN appear to be sufficiently strong to justify their use as a surrogate marker for swallowing disability in large therapeutic trials.

Predictive classifier for intensive treatment of head and neck cancer.

BACKGROUND: This study was designed to test the hypothesis that the effectiveness of intensive treatment for locoregionally advanced head and neck cancer (LAHNC) depends on the proportion of patients' overall event risk attributable to cancer. METHODS: This study analyzed 22,339 patients with LAHNC treated in 81 randomized trials testing altered fractionation (AFX; Meta-Analysis of Radiotherapy in Squamous Cell Carcinomas of Head and Neck [MARCH] data set) or chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC] data set). Generalized competing event regression was applied to the control arms in MARCH, and patients were stratified by tertile according to the ω score, which quantified the relative hazard for cancer versus competing events. The classifier was externally validated on the MACH-NC data set. The study tested for interactions between the ω score and treatment effects on overall survival (OS). RESULTS: Factors associated with a higher ω score were a younger age, a better performance status, an oral cavity site, higher T and N categories, and a p16-negative/unknown status. The effect of AFX on OS was greater in patients with high ω scores (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.85-0.99) and medium ω scores (HR, 0.91; 95% CI, 0.84-0.98) versus low ω scores (HR, 0.97; 95% CI, 0.90-1.05; P for interaction = .086). The effect of chemotherapy on OS was significantly greater in patients with high ω scores (HR, 0.81; 95% CI, 0.75-0.88) and medium ω scores (HR, 0.86; 95% CI, 0.78-0.93) versus low ω scores (HR, 0.96; 95% CI, 0.86-1.08; P for interaction = .011). CONCLUSIONS: LAHNC patients with a higher risk of cancer progression relative to competing mortality, as reflected by a higher ω score, selectively benefit from more intensive treatment.

Adjuvant external beam radiotherapy for surgically resected, nonmetastatic anaplastic thyroid cancer.

BACKGROUND: EBRT in resected, nonmetastatic anaplastic thyroid cancer (ATC) remains undefined. We evaluated patterns/outcomes with EBRT and chemotherapy in this setting. METHODS: This retrospective analysis included patients identified from the National Cancer Database with nonmetastatic ATC from 2004 to 2014 who underwent non-palliative resection. RESULTS: Our analysis included 496 patients, including 375 who underwent adjuvant EBRT (among whom 198 received concurrent chemotherapy). The median age was 68 years. On MVA, EBRT was associated with sex (OR 0.5, 95% CI 0.3-0.8, P = .002) and income (OR 2.2, 95% CI 1.4-3.3, P < .001). EBRT was associated with longer OS on UVA (12.3 vs 9.1 months, P = .004) and MVA (HR 0.7 [CI 0.6-0.9], P = .004). Concurrent chemoradiation was associated with longer OS on UVA (14.0 vs 9.1 months, P = .003) and MVA (HR 0.6 [CI 0.5-0.8], P < .001). CONCLUSION: Adjuvant EBRT is associated with longer OS in resected, nonmetastatic ATC, with additional improved survival with concurrent chemotherapy.

Synthetic Lethal Targeting of Mitotic Checkpoints in HPV-Negative Head and Neck Cancer.

Head and neck squamous cell carcinomas (HNSCC) affect more than 800,000 people annually worldwide, causing over 15,000 deaths in the US. Among HNSCC cancers, human papillomavirus (HPV)-negative HNSCC has the worst outcome, motivating efforts to improve therapy for this disease. The most common mutational events in HPV-negative HNSCC are inactivation of the tumor suppressors TP53 (>85%) and CDKN2A (>57%), which significantly impairs G1/S checkpoints, causing reliance on other cell cycle checkpoints to repair ongoing replication damage. We evaluated a panel of cell cycle-targeting clinical agents in a group of HNSCC cell lines to identify a subset of drugs with single-agent activity in reducing cell viability. Subsequent analyses demonstrated potent combination activity between the CHK1/2 inhibitor LY2606268 (prexasertib), which eliminates a G2 checkpoint, and the WEE1 inhibitor AZD1775 (adavosertib), which promotes M-phase entry, in induction of DNA damage, mitotic catastrophe, and apoptosis, and reduction of anchorage independent growth and clonogenic capacity. These phenotypes were accompanied by more significantly reduced activation of CHK1 and its paralog CHK2, and enhanced CDK1 activation, eliminating breaks on the mitotic entry of cells with DNA damage. These data suggest the potential value of dual inhibition of CHK1 and WEE1 in tumors with compromised G1/S checkpoints.

Hyperprogression after one dose of nivolumab in sinonasal cancer: A case report.

In head and neck squamous cell carcinoma, immune checkpoint inhibitors (ICI) lead to improved outcomes. There has been reports of accelerated disease progression, or hyperprogression, after ICI initiation. We present a case of hyperprogression after one dose of nivolumab in maxillary sinus squamous cell carcinoma. The patient had complete vision loss due to disease progression into the orbit, as well as intracranial invasion, lytic metastases, and new widespread distal metastases. Hyperprogression can occur after the first dose of immunotherapy. Absent biomarkers regarding individual risk of hyperprogression, caution should be exercised in using ICI in sinonasal cancers with orbital abutting disease. Laryngoscope, 130:907-910, 2020.

Multi-Institutional Validation of Deep Learning for Pretreatment Identification of Extranodal Extension in Head and Neck Squamous Cell Carcinoma.

PURPOSE: Extranodal extension (ENE) is a well-established poor prognosticator and an indication for adjuvant treatment escalation in patients with head and neck squamous cell carcinoma (HNSCC). Identification of ENE on pretreatment imaging represents a diagnostic challenge that limits its clinical utility. We previously developed a deep learning algorithm that identifies ENE on pretreatment computed tomography (CT) imaging in patients with HNSCC. We sought to validate our algorithm performance for patients from a diverse set of institutions and compare its diagnostic ability to that of expert diagnosticians. METHODS: We obtained preoperative, contrast-enhanced CT scans and corresponding pathology results from two external data sets of patients with HNSCC: an external institution and The Cancer Genome Atlas (TCGA) HNSCC imaging data. Lymph nodes were segmented and annotated as ENE-positive or ENE-negative on the basis of pathologic confirmation. Deep learning algorithm performance was evaluated and compared directly to two board-certified neuroradiologists. RESULTS: A total of 200 lymph nodes were examined in the external validation data sets. For lymph nodes from the external institution, the algorithm achieved an area under the receiver operating characteristic curve (AUC) of 0.84 (83.1% accuracy), outperforming radiologists' AUCs of 0.70 and 0.71 (P = .02 and P = .01). Similarly, for lymph nodes from the TCGA, the algorithm achieved an AUC of 0.90 (88.6% accuracy), outperforming radiologist AUCs of 0.60 and 0.82 (P < .0001 and P = .16). Radiologist diagnostic accuracy improved when receiving deep learning assistance. CONCLUSION: Deep learning successfully identified ENE on pretreatment imaging across multiple institutions, exceeding the diagnostic ability of radiologists with specialized head and neck experience. Our findings suggest that deep learning has utility in the identification of ENE in patients with HNSCC and has the potential to be integrated into clinical decision making.

Neuregulin Signaling Is a Mechanism of Therapeutic Resistance in Head and Neck Squamous Cell Carcinoma.

EGFR signaling confers resistance to radiotherapy and is a validated target in head and neck squamous cell carcinoma (HNSCC). The inhibition of EGFR in combination with radiotherapy improves local control and overall survival in these patients; however, therapeutic resistance limits the efficacy of this approach. We therefore sought to identify cellular mechanisms that cause resistance to EGFR inhibition and radiotherapy in HNSCC. Though clonal isolation of carcinoma cells exposed to increasing concentrations of cetuximab, we found that resistant cells upregulate prosurvival ErbB3 and AKT signaling. Using EFM-19 cells and confirmatory analysis of protein levels, we demonstrate that cetuximab resistance is characterized by enhanced neuregulin expression identifying a novel adaptive mechanism of therapeutic resistance. Inhibition of this autocrine loop with CDX-3379 (an ErbB3 specific antibody) was sufficient to block ErbB3/AKT signaling in cetuximab resistant cells. The combination of CDX-3379 and cetuximab reduced proliferation and survival after radiotherapy in several HNSCC cell lines. These in vitro findings were confirmed in xenograft tumor growth experiments including an approach using growth factor-supplemented Matrigel. In vivo, the delivery of EGFR and ErbB3 antibodies significantly reduced tumor growth in cetuximab-resistant FaDu and CAL27 xenografts. In summary, this work demonstrates that autocrine NRG ligand secretion is a mechanism for therapeutic resistance to cetuximab and radiotherapy. This cross-resistance to both therapeutic modalities identifies NRG as an actionable therapeutic target for improving treatment regimens in HNSCC.

Pathologic staging changes in oral cavity squamous cell carcinoma: Stage migration and implications for adjuvant treatment.

BACKGROUND: The eighth edition of the AJCC Cancer Staging Manual (AJCC 8) incorporates depth of invasion (DOI) into the pathologic tumor (pT) classification and pathologic extranodal extension (pENE) into the pathologic nodal (pN) classification for oral cavity squamous cell carcinoma (OCSCC). This study evaluated the incidence and prognostic importance of stage migration as a result of these changes in the AJCC 8 staging system. METHODS: From the National Cancer Database, cohorts were identified from patients with OCSCC undergoing definitive surgery between 2004 and 2013 for pT (n = 7184), pN (n = 13,627), and pathologic stage (pStage) analysis (n = 5580). RESULTS: DOI and pENE were prognostic in all groups except for pN3 according to the seventh edition of the AJCC Cancer Staging Manual (AJCC 7). Upstaging was seen in 12.4% of patients for the pT classification, in 13.3% for the pN classification, and in 24.8% for the overall pStage grouping. Notably, upstaging led to similar or improved 5-year overall survival (OS) for every AJCC 8 pT/N classification except pStage IVB. Patients with AJCC 7 pT1 tumors that were upstaged to AJCC 8 pT3 tumors had improved OS in comparison with the remainder of the pT3 group (71.7% vs 43.7%; P < .0001). A multivariable analysis of upstaged pT3N0 patients demonstrated a reduced risk of death with the receipt of postoperative radiotherapy (PORT; hazard ratio, 0.56; 95% confidence interval, 0.33-0.95; P = .03). CONCLUSIONS: Upstaging is common in AJCC 8, and patients with upstaged tumors demonstrate improved survival; these factors should be kept in mind when one is interpreting data with the new staging system. PORT may reduce deaths among newly upstaged pT3N0 patients, and further study is needed in this area.

Unique mutation patterns in anaplastic thyroid cancer identified by comprehensive genomic profiling.

INTRODUCTION: Anaplastic thyroid cancer (ATC) is a highly aggressive thyroid cancer. Those ATC with genomic alterations (GAs) in TSC2, ALK, and BRAF may respond to targeted therapies. METHODS: Comprehensive genomic profiling on 90 ATC specimens identified base substitutions, short insertions and deletions, amplifications, copy number alterations, and genomic rearrangements in up to 315 cancer-related genes and 28 genes commonly rearranged in cancer. RESULTS: Median patient age was 65 (range, 33-86) years, 50 patients were male. There was a mean of 4.2 GA per case, range 1-11. The most common GA were TP53 (66%), BRAF (34%), TERT (32%), CDKN2A (32%), and NRAS (26%). BRAF V600E and NRAS/HRAS/KRAS alteration were mutually exclusive. BRAF, CDKN2A, PIK3CA, and JAK2 were more frequent in patients >70 years of age; while myc, PTEN, and NRAS were more common in those ≤50 years. CONCLUSION: ATC shows many GA with potential therapeutic significance and suggesting different molecular pathways can lead to ATC.

Radiation therapy treatment facility and overall survival in the adjuvant setting for locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Treatment at high-volume surgical facilities (HVSFs) provides a survival benefit for patients with head and neck squamous cell carcinomas (HNSCCs); however, it is unknown what role postoperative radiation therapy (PORT) plays in achieving the improved outcomes. METHODS: From the National Cancer Database, 6844 patients with locally advanced invasive HNSCCs of the oral cavity, oropharynx, larynx, and hypopharynx who underwent definitive surgery with PORT between 2004 and 2013 were identified. HVSFs were those in the top percentile for annual case volume during this period. RESULTS: The median follow-up was 54 months. Compared with a lower volume surgical facility (LVSF), an HVSF improved 5-year overall survival (OS; 57.7% at HVSFs vs 52.5% at LVSFs; P = .0003). Overall, 31.6% of the patients changed their radiation therapy (RT) facility after surgery, with this being more common at HVSFs (39.1% vs 28.9% at LVSFs; P < .001). Among those patients undergoing surgery at an HVSF, remaining at the same facility for RT improved 5-year OS (63.1% vs 49.3% with a facility change; P < .0001). A propensity score-matched cohort of patients treated at HVSFs confirmed the improved 5-year OS when patients remained at the treating HVSF for RT (59.2% vs 50.7% with a facility change; P = .005). In a multivariate analysis, treatment at an HVSF and remaining there for RT resulted in a reduced hazard of death (hazard ratio, 0.81; 95% confidence interval, 0.69-0.94; P = .006). CONCLUSIONS: The survival benefit associated with HVSFs persists only when patients remain at the facility for RT, and this suggests that facility specialization and/or high-volume PORT may assist in driving the OS improvement.

HPV status in unknown primary head and neck cancer: Prognosis and treatment outcomes.

OBJECTIVES: Approximately 3% to 9% of head and neck cancer presents with a metastatic node and no identifiable primary tumor. These cases of head and neck carcinoma of unknown primary (HNCUP) present a therapeutic challenge. Therapy of this disease varies based on factors such as institutional, surgeon, and patient preference. Evidence demonstrating the outcomes associated with these therapies for HNCUP is limited, and among the available series, the tumor human papillomavirus (HPV) status is often ignored. Treatment deintensification has been proposed for a subset of these patients. We aim to evaluate the treatment-related outcomes for HPV-associated and HPV-negative HNCUP. METHODS: A retrospective study of 978 adult HNCUP diagnosed from 2010 to 2013 in the NCDB was conducted. Multivariate Cox survival regressions as well as univariate Kaplan-Meier analyses were conducted. RESULTS: Patients with HPV-associated disease had superior survival, with a 3-year survival of 94.8% (standard error [SE]: 1.0), compared with 80.3% (SE: 2.9) among those with HPV-negative disease. Among HPV-negative patients with clinical nodal classification (cN)2/cN3 disease, treatment with definitive radiotherapy alone compared to definitive chemoradiotherapy was associated with diminished survival (hazard ratio 5.507, P = 0.005). Among patients with HPV-associated cancer and cN2/cN3 disease, all treatments (surgery alone, surgery with adjuvant radiotherapy, surgery with adjuvant chemoradiotherapy, definitive chemoradiotherapy, definitive radiotherapy) resulted in statistically equivalent survival. CONCLUSION: Tumor HPV status has a significant prognostic value for HNCUP and should be considered in future studies of treatment deintensification in this group. Treatment deintensification to radiotherapy alone in cN2/cN3 cases may result in poorer patient survival for HPV-negative patients, whereas it may be a promising option for further investigation in HPV-positive patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:684-691, 2019.